Project Summary According to the World Health Organization, Cardiovascular disease (CVD) is responsible for 31% of deaths worldwide making it the largest global cause of mortality. These numbers are reflected in the United states where over 600,000 people died of CVD. CVD is an inflammatory disease that often leads to mortality by thrombosis and platelets mediate both the inflammatory and thrombotic aspects of CVD. Our laboratory studies the Triggering receptor expressed in myeloid cells or (TLT-1) that is stored in the ??granules of the platelets and is both expressed to the platelet surface and released after platelet activation. TLT-1 binds fibrinogen. While TLT-1 has demonstrated roles in Cardiovascular disease, sepsis, and acute lung injury, its interaction with fibrinogen is poorly understood. We hypothesize that TLT-1?s interaction with fibrinogen is a major pathway by which the immune system commandeers the hemostatic system for immune function. In this application we propose to mechanistically define this interaction and demonstrate is usefulness as a therapeutic target. We propose the following three aims: Aim I ? Determine the relative contribution of fibrinogen binding to TLT-1 and ?IIb?2 using double deficient (treml1-/-/itga2b-/-) mice; Aim II - Elucidate TLT-1 signaling pathways; Aim III ? Evaluate the effect of TLT-1 prophylactics on the progression of CVD and obesity. At the completion of these aims we will have defined TLT-1?s contribution to platelet interaction with fibrinogen and is potential as a therapeutic target.